Rho激酶抑制剂对大鼠压力负荷性心力衰竭保护作用的研究  

To explore the protective effect of Rho kinase inhibitor on rats with pressure overload heart failure

作　　者：张晓平 徐峰[1] ZHANG Xiao-ping;XU Feng(Department of Cardiology,The First Hospital of China Medical University;The Central Hosiptal of Shenyang Medical University,Shenyang Liaoning 110001,China)

机构地区：[1]中国医科大学附属第一医院心内科 [2]沈阳医学院附属中心医院电诊科,辽宁沈阳110001

出　　处：《临床和实验医学杂志》2018年第8期796-799,共4页Journal of Clinical and Experimental Medicine

摘　　要：目的探讨Rho激酶抑制剂对大鼠压力负荷性心力衰竭模型中的抗氧化机制。方法 80只普通级8周龄雄性SD大鼠分成假手术组、手术组;手术中依据干预方式将手术组平行分成三组:安慰剂组、盐酸法舒地尔2 mg/(kg·d)组(低剂量给药组)和盐酸法舒地尔10 mg/(kg·d)组(高剂量给药组)。建立压力负荷心力衰竭大鼠模型,然后分别给予以下处理。假手术组:生理盐水10 mg/kg腹腔注射,每日1次;安慰剂组:生理盐水10 mg/kg腹腔注射,每日1次;低剂量给药组:盐酸法舒地尔2 mg/kg腹腔注射,每日2次;高剂量给药组:盐酸法舒地尔10 mg/kg腹腔注射,每日2次。所有大鼠术后干预3周,饲养至第7周后,测量每组剩余大鼠心脏重量指数,并分别通过Western blot法和Realtime PCR法测量不同剂量盐酸法舒地尔干预时氧化应激指标黑色素瘤分化相关基因5(MDA5)、肌醇依赖酶1(IRE1α)、氧化应激指标超氧化物歧化酶-1(SOD-1),氧化应激核转录相关因子-2/Kelch样ECH相关蛋白-1 Nrf2/Keap1通路指标Nrf2和Keap1的蛋白及mRNA表达。结果建立压力负荷性心力衰竭模型后,安慰剂组、低剂量给药组及高剂量给药组中,大鼠氧化应激指标MDA5、IRE1α蛋白表达及其mRNA水平表达均明显升高,抗氧化应激指标SOD-1蛋白表达及其mRNA水平均明显降低,且大鼠氧化应激Nrf2/Keap1通路蛋白Nrf2、Keap1的mRNA水平及蛋白表达量均明显升高,与假手术组相比差异具有统计学意义(P<0.05)。应用盐酸法舒地尔处理后,MDA5、IRE1α蛋白及其mRNA水平均明显降低,SOD-1蛋白及其mRNA水平均明显升高(P<0.05);Nrf2、Keap1的蛋白及其mRNA水平均明显上调(P<0.05),且高剂量给药组上调效果明显高于低剂量给药组(P<0.05)。结论 Rho激酶抑制剂通过降低压力负荷性心力衰竭大鼠促氧化应激MDA5和IRE1α蛋白表达,提高抗氧化应激SOD-1蛋白表达,并通过调控氧化应激Nrf2/Keap1通路影响氧化应激反应,其调节�Objective To investigate the antioxidant mechanism of Rho kinase inhibitor in rat model of heart failure.Methods 80 SD rats were randomly divided into sham operation group and operation group;The operation group was divided into three groups according to the way of intervention:the placebo group,2 mg/kg/d group(low dose group)and 10 mg/(kg·d)group(high dose group).To establish a rat model of pressure overload heart failure:Sham operation group:intraperitoneal injection of saline 10 mg/kg,1 times/day.The placebo group:Intraperitoneal injection of saline 10 mg/kg,1 times/day;Low dose group:fasudil injection of 2 mg/kg,2 times/day.High dose group:fasudil injection of 10 mg/kg,2 times/day,intervene for 3 weeks.After treatment for 7 weeks,the mRNA and protein expression of MDA5,IRE1α,Nrf2,Keap1 and SOD-1 in different doses of Fasudil intervention were observed.Results After establishment of the model of ascending aortic constriction,the mRNA and protein expression of oxidative stress index MDA5,IRE1αwere significantly increased in placebo group,low dose group and high dose group.While the mRNA and protein expression of antioxidant stress index SOD-1 were significantly lower.And level of Nrf2 and Keap1 were significantly increased compared with the sham operation group(P<0.05).After the intervention of fasudil,the expression of MDA5,IRE1αwere significantly decreased.And the level of SOD-1 were significantly increased(P<0.05).The mRNA and protein expression of Nrf2 and Keap1 were significantly increased(P<0.05),and high dose group was significantly higher than that of dose group(P<0.05).Conclusion Rho kinase inhibitor can enhance the expression of SOD-1 protein by reducing the expression of MDA5 and IRE1αprotein,and can regulate the Nrf2/keap1 pathway to control the response of oxidative stress and improve the function of heart.And the regulatory effect may be dose-dependent with Rho kinase inhibitors.

关 键 词：大鼠 压力负荷性心力衰竭 RHO激酶 氧化应激 MDA5 IRE1α SOD-1 Nrf2/Keap1 

分 类 号：R-332[医药卫生] R541.6